Type 2 diabetes (T2D) is already placing a major burden on the US healthcare system and projections indicate the problem will get worse. It is therefore of great importance to further our understanding of the molecular mechanisms that contribute to the onset and establishment of T2D and its complications. This application proposes research and training plans for Dr. Leung to become a leading independent investigator in the field of diabetes. While the applicant has had extensive training in molecular biology and simple model organisms, her development and future success as an investigator will require additional practical skills and knowledge regarding advanced mouse models, mouse physiology and metabolism. To attain the necessary skills and knowledge, she has assembled a strong mentoring team comprising of a group of expert senior investigators and proposed a detailed list of career development and training activities. The mentors: Drs. Natarajan, Tontonoz, Rossi, and Lusis, represent a diverse set of investigators with a track record of successful mentoring and diabetes related research. They will provide guidance and assistance with Dr. Leung's research and training in the development of Dr. Leung's academic career as she transitions to an independently funded investigator. Over the course of this award, she will also engage in additional training activities including structured postgraduate courses intended to increase knowledge and skills in mouse metabolism and physiology, grant-writing workshops, laboratory management workshops, and teaching. The research activities proposed in this application will investigate the role of long non-coding RNAs (lncRNAs) in the development of insulin resistance, dysregulation of gluconeogenesis, and ultimately, T2D. This project is based on extensive preliminary data demonstrating that specific lncRNAs are dysregulated in livers of insulin resistant mice. The overarching hypothesis of this application is that lncRNAs are involved in modulating key genes that regulate insulin signaling pathways and hepatic glucose production, and that dysregulation of these lncRNAs can contribute to the development of insulin resistance and dysregulation of hepatic glucose production. The Specific Aims are: 1) to identify lncRNAs that are dysregulated in livers of diabetic mice, including both genetic and non-genetic mouse models, 2) to determine the functional consequences of altered expression of lncRNAs in the livers of diabetic mice, and 3) to characterize the mechanism of action and regulation of candidate lncRNAs in livers under diabetic conditions. The results from the proposed studies will provide significant new insights into the molecular mechanisms that accompany the development of hepatic insulin resistance and T2D and will form the basis of future grant applications from the applicant. This project will furthermore provide Dr. Leung with the necessary experience for her development into an independent scientist.